4-Oxa and 4-thia steroids

ABSTRACT

The compounds of the present invention are those of structural formula (I) ##STR1## wherein X is oxygen or sulfur. Pharmaceutical compositions and methods of use of the compounds in the treatment of hyperandrogenic conditions are disclosed. In addition, the combination of the compounds with other active agents such as finasteride, minoxidil and retinoic acid or a derivative thereof is disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the national phase application under 35U.S.C. §371 of PCT application Serial No. PCT/US96/16883, filed Oct. 22,1996, based on provisional application 60/006,001, filed Oct. 26, 1995.

FIELD OF THE INVENTION

The present invention provides novel compounds, novel compositions,methods of their use and methods of their manufacture, where suchcompounds are generally pharmacologically useful as agents in therapieswhose mechanism of action rely on the inhibition of 5α-reductase.

BACKGROUND OF THE INVENTION

Certain undesirable physiological manifestations, such as acne vulgaris,seborrhea, female hirsutism, androgenic alopecia which includes femaleand male pattern baldness, and benign prostatic hyperplasia, are theresult of hyperandrogenic stimulation caused by excessive accumulationof testosterone ("T") or similar androgenic hormones in the metabolicsystem. Androgenic alopecia is also known as androgenetic alopecia.Early attempts to provide a chemotherapeutic agent to counter theundesirable results of hyperandrogenicity resulted in the discovery ofseveral steroidal antiandrogens having undesirable hormonal activitiesof their own. The estrogens, for example, not only counteract the effectof the androgens but have a feminizing effect as well. Non-steroidalantiandrogens have also been developed, for example,4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al.,Endocrinol. 1972, 91 (2). However, these products, though devoid ofhormonal effects, compete with all natural androgens for receptor sites,and hence have a tendency to feminize a male host or the male fetus of afemale host and/or initiate feed-back effects which would causehyperstimulation of the testes.

The principal mediator of androgenic activity in some target organs,e.g. the prostate, is 5α-dihydrotestosterone ("DHT"), formed locally inthe target organ by the action of testosterone-5α-reductase. Inhibitorsof testosterone-5α-reductase will serve to prevent or lessen symptoms ofhyperandrogenic stimulation in these organs. See especially U.S. Pat.No. 4,377,584, issued Mar. 22, 1983, and U.S. Pat. No. 4,760,071, issuedJul. 26, 1988, both assigned to Merck & Co., Inc.

The enzyme 5α-reductase catalyzes the reduction of testosterone to themore potent androgen, dihydrotestosterone, as shown below: ##STR2##

Finasteride,(17β-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5α-androst-1-ene-3-one) asshown below, is a potent inhibitor of the human prostate enzyme.##STR3## Under the trade name PROSCAR®, finasteride is known to beuseful in the treatment of hyperandrogenic conditions; see eg. U.S. Pat.No. 4,760,071. Finasteride is currently prescribed for the treatment ofbenign prostatic hyperplasia (BPH), a condition afflicting to somedegree the majority of men over age 55. Finasteride's utility in thetreatment of androgenic alopecia and prostatic carcinoma is alsodisclosed in the following documents: EP 0 285,382, published Oct. 5,1988; EP 0 285,383, published Oct. 5, 1988; Canadian Patent no.1,302,277; and Canadian Patent no. 1,302,276.

There are two isozymes of 5α-reductase in humans. One isozyme (type 1 or5α-reductase 1) predominates in sebaceous glands of facial and skintissue and is relatively insensitive to finasteride (see, e.g., G.Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791(November 1992)); the other (type 2 or 5α-reductase 2) predominates inthe prostate and is potently inhibited by finasteride.

Since 5α-reductase and its isozymes convert testosterone to DHT,inhibition of either or both of the isozymes would serve to alleviatethe conditions and diseases mediated by DHT. The present inventionaddresses this by providing novel compounds that are active asinhibitors of 5α-reductase.

SUMMARY OF THE INVENTION

The novel compounds of the present invention are those of structuralformula I: ##STR4## wherein X is selected from O and S, or apharmaceutically acceptable salt, ester, or stereoisomer thereof, andare inhibitors of 5α-reductase. The compounds of formula I are useful inthe oral, systemic, parenteral or topical treatment of hyperandrogenicconditions such as acne vulgaris, seborrhea, androgenic alopecia whichincludes female and male pattern baldness, female hirsutism, benignprostatic hyperplasia, and the prevention and treatment of prostaticcarcinoma, as well as in the treatment of prostatitis.

Therefore it is an object of this invention to provide compounds thathave sufficient activity in the inhibition of 5α-reductase. It is anadditional object of this invention to provide methods of using thecompounds of formula I for the treatment of hyperandrogenic conditionssuch as acne vulgaris, seborrhea, androgenic alopecia, male patternbaldness, female hirsutism, benign prostatic hyperplasia, and theprevention and treatment of prostatic carcinoma, as well as thetreatment of prostatitis. It is a further object of this invention toprovide pharmaceutical compositions for the compounds of formula I.Another object of this invention is to provide compounds of formula I incombination with other active agents, for example with finasteride, or apotassium channel opener, such as minoxidil, or a retinoic acid or aderivative thereof, wherein such combinations would be useful in one ormore of the above-mentioned methods of treatment or pharmaceuticalcompositions.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention have the structural formula I:##STR5## or a pharmaceutically acceptable salt, ester or stereoisomerthereof, wherein:

the C5-C6 bond designated with a dotted line independently represents asingle or double bond, provided that when the C5-C6 is a double bond,H_(a) is absent and when the C5-C6 bond is a single bond H_(a) ispresent and represents hydrogen;

X is selected from oxygen and sulfur;

R¹ is selected from hydrogen and C₁₋₅ alkyl;

R² is selected from CH₃, CH₂ OR³, and H;

R³ is selected from: C₁₋₅ alkyl;

Z is ##STR6## A¹ is selected from: (1) --H,

(2) keto,

(6) carboxy,

(7) protected amino,

(8) amino,

(9) C₁₋₁₀ alkyl,

(10) substituted or unsubstituted C₂₋₁₀ alkenyl,

(11) aryl-substituted C₁₋₁₀ alkyl,

(12) aryl or heteroaryl,

(13) substituted aryl or heteroaryl,

(14) aryl or heteroaryl carbamoyl-substituted C₁₋₁₀ alkyl,

(15) C₁₋₁₀ alkylcarbonyl,

(16) aryl or heteroaryl carbonyl,

(17) ether-substituted C₁₋₁₀ alkyl,

(18) thioether-substituted C₁₋₁₀ alkyl,

(19) keto-substituted C₁₋₁₀ alkyl,

(20) heteroaryl-substituted C₁₋₁₀ alkyl,

(21) carboxylic ester,

(22) carboxamide, including substituted and unsubstituted anilidederivatives,

(23) urea,

(24) C₁₋₁₀ alkylureido C₀₋₅ alkyl,

(25) substituted or unsubstituted heteroaryl or arylureidoC₀₋₅ alkyl,

(26) C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl,

(27) C₁₋₁₀ alkylcarbonylamino,

(28) alkanoylamidoalkyl

(29) ether,

(30) thio ether, and

(31) substituted and unsubstituted aryl or heteroaryl ether;

A² is selected from:

(1) --H,

(2) keto,

(3) protected hydroxy,

(4) acetate,

(5) hydroxy,

(6) carboxy,

(7) protected amino,

(8) amino,

(9) C₁₋ alkyl,

(10) substituted or unsubstituted C₂₋₁₀ alkenyl,

(11) aryl-substituted C₁₋₁₀ alkyl,

(12) aryl or heteroaryl,

(13) substituted aryl or heteroaryl,

(14) aryl or heteroaryl carbamoyl-substituted C₁₋₁₀ alkyl,

(15) C₁₋₁₀ alkylcarbonyl,

(16) aryl or heteroaryl carbonyl,

(17) ether-substituted C₁₋₁₀ alkyl,

(18) thioether-substituted C₁₋₁₀ alkyl,

(19) keto-substituted C₁₋₁₀ alkyl,

(20) heteroaryl-substituted C₁₋₁₀ alkyl,

(21) carboxylic ester,

(22) carboxamide, including substituted and unsubstituted anilidederivatives,

(23) urea,

(24) C₁₋₁₀ alkylureido C₀₋₅ alkyl,

(25) substituted or unsubstituted arylureidoC₀₋₅ alkyl,

(26) C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl,

(27) C₁₋₁₀ alkylcarbonylamino,

(28) alkanoylamidoalkyl,

(29) ether,

(30) thio ether, and

(31) substituted and unsubstituted aryl- or heteroaryl-ether;

Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl,pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl andbenzofuranyl.

Preferred are compounds wherein:

(a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy,trimethylsilyloxy, tri-ethylsilyloxy, triisopropylsilyloxy, andtriphenylsilyloxy;

(b) protected amino is acetylamino, benzoylamino, and pivaloylamino;

(c) C₁₋₁₀ alkyl is selected from methyl, ethyl, propyl, butyl, pentyl,1,5-dimethylhexyl, 6-methylhept-2-yl, 5-methylhexyl, and1-methyl-4-isopropylhexyl;

(d) substituted or unsubstituted C₂₋₁₀ alkenyl is selected from:phenylmethylene, chlorophenylmethylene, ethoxycarbonylphenylmethylene,carboxyphenylmethylene,(((1,1-dimethylethyl)amino)carbonyl)phenylmethylene, trimethoxyphenylmethylene, methoxyphenylmethylene, methylsulfonylphenylmethylene,biphenylmethylene, nitrophenylmethylene, aminophenylmethylene,acetylaminophenylmethylene, pivaloylaminophenylmethylene,phenoxyphenylmethylene, 2-imidazolyl methylene, 2-thiazolylmethylene,

(e) aryl substituted C₁₋₁₀ alkyl is selected from omega-phenylpropyl and1-(chlorophenoxy)ethyl;

(f) aryl is selected from phenyl, and naphthyl;

(g) substituted aryl or heteroaryl is selected from phenyl, pyridyl andpyrimidinyl substituted with one to three substituents independentlyselected from:

(1) --H,

(2) --OH,

(3) --CH₃,

(4) --OCH₃,

(5) --S(O)_(n) --CH₃, wherein n is selected from 0, 1, and 2,

(6) --CF₃,

(7) halo,

(8) --CHO,

(9) CN,

(10) phenyloxy,

(11) ethyl,

(12) t-butyl,

(13) OCH₂ CH₃,

(14) OC(CH₃)₃, and

(15) --NHR⁷, wherein R⁷ is selected from: --H, --C₁₋₈ alkyl, --C₁₋₆alkylcarbonyl, --C₁₋₆ alkylsulfonyl, and --C₁₋₆ alkoxycarbonyl,

(h) aryl or heteroaryl carbamoyl substituted C₁₋₁₀ alkyl is selectedfrom 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl-ethyl;

(i) C₁₋₁₀ alkylcarbonyl is selected from isobutylcarbonyl andisopropylcarbonyl;

(j) aryl or heteroaryl carbonyl is selected from phenylcarbonyl andpyridyl carbonyl;

(k) ether-substituted C₁₋₁₀ alkyl is selected from 1-methoxy-ethyl and1-ethoxy-ethyl;

(l) thioether-substituted C₁₋₁₀ alkyl is selected from1-methylthio-ethyl, and 1-ethylthio-ethyl;

(m) keto-substituted C₁₋₁₀ alkyl is 1-keto-ethyl, ketomethyl,1-ketopropyl, and ketobutyl;

(n) heteroaryl-substituted C₁₋₁₀ alkyl is omega-(4-pyridyl)butyl;

(o) carboxylic esters are C₁₋₁₀ alkylcarboxylic esters selected fromcarbomethoxy and carboethoxy;

(p) carboxamides are selected from N,N-diisopropyl carboxamide,N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-diphenylmethyl)carboxamide, N-(diphenylmethyl)-carboxamide,N-t-butyl carboxamide, N-isopropyl carboxamide, 1-adamantyl carboxamide,2-adamantyl carboxamide and N-(substituted phenyl)carboxamides whereinthe phenyl may be substituted with 1 to 2 substitutents selected fromethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I);

(q) C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl is selected from acetyloxymethyl,trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl;

(r) urea is t-butylcarbonylamino urea;

(s) C₁₋₁₀ alkylureido C₀₋₅ alkyl is selected from:N-t-butylureidomethyl, N-n-propylureidomethyl, N-n-octylureidomethyl,N-isopropylureido, allylureido,

(t) substituted or unsubstituted arylureidoC₀₋₅ alkyl is selected from:N-(ethylphenyl)ureidomethyl, N-(chlorophenyl)ureidomethyl,N-phenylureidomethyl, N-(dichlorophenyl)ureidomethyl,N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl,N-thien-2-ylmethylureidomethyl, N-(fluorophenyl)ureido,N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl;

(u) C₁₋₁₀ alkylcarbonylamino is t-butylcarbonylamino;

(v) alkanoylamidoalkyl is selected from: trimethylacetamidomethyl,carbomethoxyoctanoylamidomethyl, (isobutylphenyl)propionamidomethyl,8-carboxyoctanoylamidomethyl, bromohexanoylamido methyl,hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl,isopropylthioacetamidomethyl, benzyloxyacetamidomethyl,carbomethoxyacetamidomethyl, triphenylproprionamidomethyl,cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl,(3-hydroxy-4,4,4-trichlorobutyramido)methyl, andphenylthioacetamidomethyl;

(w) ether is selected from ethylene ketal, and C₁₋₈ alkyl etheroptionally substituted with hydroxy, halo, C₁₋₈ alkoxy, C₂₋₆ alkenyl, oraryl;

(x) thioether is selected from: C₁₋₈ alkylthio, phenylthio, and C₁₋₈alkylthio substituted with phenyl; and

(y) substituted and unsubstituted aryl or heteroaryl ether is selectedfrom thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy,chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy,methylsulfonylphenyloxy and pyrimidinyloxy.

In one embodiment of the instant invention are compounds of formula Iwherein X is oxygen.

In one class of the compounds of this embodiment are compounds wherein Zis ##STR7##

Exemplifying this class are:

(1) N-t-Butyl-4-oxa-5α-androst-1-en-3-one-17β-carboxamide,

(2) 7β-Methyl-4-oxa-5α-cholest-1-en-3-one,

(3)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(4)17β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(5)17β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(6)17β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(7) 17β-(N-tert-amylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(8) 17β-(N-tert-hexylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(9) 17β-(N-isobutylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(10) 17β-(N-tert-octylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(11) 17β-(N-1,1-diethylbutylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(12) 17β-(N-neopentylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(13) 17β-(N-2-adamantylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(14) 17β-(N-1-adamantylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(15) 17β-(N-2-norbornylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(16) 17β-(N-1-norbornylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(17) 17β-(N-phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(18) 17β-(N-benzylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(19)17β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one,

(20)17β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one,

(21)17β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one,

(22) 17β-(N-n-octylcarbamoyl)-4-methyl-4-oxa-5α-androst-1-en-3-one,

(23) 17β-(1-methoxyethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one

(24) 17β-(isopropyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(25) 17β-(4-methyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(26)17β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(27)17β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(28) 17β-(4-chlorophenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(29) 17β-(2-pyrimidinyloxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one, and

(30)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one.

Further exemplifying this class are:

(1) N-t-Butyl-4-oxa-5α-androst-1-en-3-one-17β-carboxamide,

(2) 7β-Methyl4-oxa-5α-cholest-1-en-3-one,

(3)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one,

(4) 17β-(N-phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(5) 17β-(N-benzylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(6) 17β-(1-methoxyethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one

(7) 17β-(isopropyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(8) 17β-(4-methylphenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(9)17β-(1-(3-chlorophenyoxy)ethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(10)17β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(11) 17β-(methyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one

(12) 17β-(4-chlorophenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(13) 17β-(2-pyrimidinyloxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one, and

(14)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one.

In one subclass of this class of the invention are compounds wherein R¹is hydrogen, R² is selected from H and CH₃, and A¹ is selected from:carboxamide, including substituted and unsubstituted anilidederivatives.

Further illustrating this subclass are compounds wherein carboxamide isselected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-(diphenylmethyl)carboxamide,N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropylcarboxamide, 1-adamantyl carboxamide, 2-adamantyl carboxamide, andN-(substituted phenyl)carboxamides wherein the phenyl may be substitutedwith 1 to 2 substitutents selected from ethyl, methyl, trifluoromethylor halo (F, Cl, Br, I).

Still further illustrating this subclass are compounds whereincarboxamide is --C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl).

In one subclass of this class of the invention are compounds wherein R¹is hydrogen, R² is selected from H and CH₃, the C5-C6 bond designatedwith a dotted line is a single bond, H_(a) is present and representshydrogen, and A¹ is selected from: carboxamide, including substitutedand unsubstituted anilide derivatives.

Further illustrating this subclass are compounds wherein carboxamide isselected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-(diphenylmethyl)carboxamide,N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropylcarboxamide, 1-adamantyl carboxamide, 2-adamantyl carboxamide, andN-(substituted phenyl)carboxamides wherein the phenyl may be substitutedwith 1 to 2 substitutents selected from ethyl, methyl, trifluoromethylor halo (F, Cl, Br, I).

Still further illustrating this subclass are compounds whereincarboxamide is --C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl).

In one subclass of this class of the invention are compounds wherein R¹is hydrogen, R² is selected from H and CH₃, the C5-C6 bond designatedwith a dotted line is a double bond, H_(a) is absent, and A¹ is selectedfrom: carboxamide, including substituted and unsubstituted anilidederivatives.

Further illustrating this subclass are compounds wherein carboxamide isselected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-(diphenylmethyl)carboxamide,N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropylcarboxamide, 1-adamantyl carboxamide, 2-adamantyl carboxamide andN-(substituted phenyl)carboxamides, wherein the phenyl may besubstituted with 1 to 2 substitutents selected from ethyl, methyl,trifluoromethyl or halo (F, Cl, Br, I).

Still further illustrating this subclass are compounds whereincarboxamide is --C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl).

In another subclass of this class of the invention are compounds whereinR¹ is CH₃, R² is selected from H and CH₃, and A¹ is a selected from:carboxamide, including substituted and unsubstituted anilidederivatives, and C₁₋₁₀ alkyl. Further illustrating this subclass arecompounds wherein carboxamide is --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl) and C₁₋₁₀ alkyl is selected fromisopropyl, isobutyl, 1,5-dimethylhexyl, and 5-methylhexyl.

In another class of the compounds of this embodiment are compoundswherein Z is ##STR8##

Exemplifying compounds of this class are:

(1) N-t-Butyl-4-oxa-5α-androst-1-en-3-one-16β-carboxamide,

(2) 16β-(1,5-dimethylhexyl)-7β-Methyl-4-oxa-5α-androst-1-en-3-one,

(3)16β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one,

(4) 16β-(N-tert-amylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(5) 16β-(N-tert-hexylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(6) 16β-(N-isobutylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(7) 16β-(N-tert-octylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(8) 16β-(N-1,1-diethylbutylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(9) 16β-(N-neopentylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(10) 16β-(N-2-adamantylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(11) 16β-(N-1-adamantylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(12) 16β-(N-2-norbomylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(13) 16β-(N-1-norbomylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(14) 16β-(N-phenylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(15) 16β-(N-benzylcarbamoyl)-4-oxa-5α-androst-1-en-3-one,

(16)16β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one,

(17)16β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one,

(18)16β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one,

(19)16β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one,

(20)16β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one,

(21)16β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one,

(22) 16β-(N-n-octylcarbamoyl)-4-methyl-4-oxa-5α-androst-1-en-3-one,

(23) 16β-(1-methoxyethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one

(24) 16β-(isopropyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(25) 16β-(4-methyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(26)16β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(27)16β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(28) 16β-(4-chlorophenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

(29) 16β-(2-pyrimidinyloxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one, and

(30)16β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-oxa-5.alpha.-androst-1-en-3-one.

Further exemplifying the compounds of this class are:

16β-(4-methyl-phenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

16β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-oxa-5α-androst-1-en-3-one,

16β-(4-methylsulfonyl-phenoxy)-7β-methyl4-oxa-5α-androst-1-en-3-one,

16β-(4-chlorophenoxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one, and

16β-(2-pyrimidinyloxy)-7β-methyl-4-oxa-5α-androst-1-en-3-one.

In one subclass of this class, R¹ is C₁₋₅ alkyl, R² is selected fromhydrogen and methyl, and A² is selected from: alkoxy, aryloxy, eitherunsubstituted or substituted, heteroaryloxy, either substituted orunsubstituted, and alkyl, either unsubstituted or substituted.

Further illustrating this subclass are compounds wherein, A² is selectedfrom: substituted aryloxy, and heteroaryloxy, either substituted orunsubstituted.

Exemplifying compounds of this subclass are compounds wherein the C5-C6bond designated with a dotted line is a single bond, and H_(a) ispresent and represents hydrogen.

Further exemplifying the compounds of this subclass are compoundswherein the C5-C6 bond designated with a dotted line is a double bond,and H_(a) is absent.

In one subclass of this class, R¹ is H or CH₃, R² is selected from H andCH₃, and A² is selected from: substituted and unsubstituted aryl orheteroaryl ether. Further illustrating this subclass are the compoundswherein substituted and unsubstituted aryl or heteroaryl ether isselected from thiophenoxy, biphenyloxy, acetamidophenoxy,(3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy,hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy. Stillfurther illustrating the compounds of the present invention arecompounds wherein substituted or unsubstituted aryl or heteroaryl etheris selected from 4-methyl-phenoxy, 4-chlorophenoxy, and2-pyrimidinyloxy.

In another embodiment of the instant invention are compounds of formulaI wherein X is sulfur.

In one class of the compounds of this embodiment are compounds wherein Zis ##STR9##

Exemplifying compounds of this class are:

(1) N-t-Butyl-4-thia-5α-androst-1-en-3-one-17β-carboxamide,

(2) 7β-Methyl-4-thia-5α-cholest-1-en-3-one,

(3)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(4)17β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(5)17β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(6)17β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(7) 17β-(N-tert-amylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(8) 17β-(N-tert-hexylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(9) 17β-(N-isobutylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(10) 17β-(N-tert-octylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(11) 17β-(N-1,1-diethylbutylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(12) 17β-(N-neopentylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(13) 17β-(N-2-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(14) 17β-(N-1-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(15) 17β-(N-2-norbomylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(16) 17β-(N-1-norbomylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(17) 17β-(N-phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(18) 17β-(N-benzylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(19)17β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(20)17β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(21)17βp-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(22) 17β-(N-n-octylcarbamoyl)-4-methyl-4-thia-5α-androst-1-en-3-one,

(23) 17β-(1-methoxyethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(24) 17β-(isopropyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(25) 17β-(4-methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(26)17β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(27)17β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(28) 17β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(29) 17β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, and

(30)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one.

Further exemplifying compounds of this class are:

(1) N-t-Butyl-4-thia-5α-androst-1-en-3-one-17β-carboxamide,

(2) 7β-Methyl-4-thia-5α-cholest-1-en-3-one,

(3)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,

(4) 17β-(N-phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(5) 17β-(N-benzylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(6) 17β-(1-methoxyethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(7) 17β-(isopropyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(8) 17β-(4-methylphenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(9)17β-(1-(3-chlorophenyoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(10)17β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(11) 17β-(methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(12) 17β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(13) 17β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, and

(14)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one.

In one subclass of this class of the invention are compounds wherein R¹is hydrogen, R² is selected from H and CH₃, and A¹ is selected from:carboxamide, including substituted and unsubstituted anilidederivatives.

Further illustrating this subclass are compounds wherein carboxamide isselected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-(diphenylmethyl)carboxamide,N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropylcarboxamide, 1-adamantyl carboxamide, 2-adamantyl carboxamide, andN-(substituted phenyl)carboxamides wherein the phenyl may be substitutedwith 1 to 2 substitutents selected from ethyl, methyl, trifluoromethylor halo (F, Cl, Br, I).

Still further illustrating this subclass are compounds whereincarboxamide is --C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl).

In one subclass of this class of the invention are compounds wherein R¹is hydrogen, R² is selected from H and CH₃, the C5-C6 bond designatedwith a dotted line is a single bond, H_(a) is present and representshydrogen, and A¹ is selected from: carboxamide, including substitutedand unsubstituted anilide derivatives.

Further illustrating this subclass are compounds wherein carboxamide isselected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-diphenylmethyl)carboxamide, N-(diphenylmethyl)-carboxamide,N-t-butyl carboxamide, N-isopropyl carboxamide, 1-adamantyl carboxamide,2-adamantyl carboxamide, and N-(substituted phenyl)carboxamides whereinthe phenyl may be substituted with 1 to 2 substitutents selected fromethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).

Still further illustrating this subclass are compounds whereincarboxamide is --C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl).

In one subclass of this class of the invention are compounds wherein R¹is hydrogen, R² is selected from H and CH₃, the C5-C6 bond designatedwith a dotted line is a double bond, H_(a) is absent, and A¹ is selectedfrom: carboxamide, including substituted and unsubstituted anilidederivatives.

Further illustrating this subclass are compounds wherein carboxamide isselected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-(diphenylmethyl)carboxamide,N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropylcarboxamide, 1-adamantyl carboxamide, 2-adamantyl carboxamide andN-(substituted phenyl)carboxamides, wherein the phenyl may besubstituted with 1 to 2 substitutents selected from ethyl, methyl,trifluoromethyl or halo (F, Cl, Br, I).

Still further illustrating this subclass are compounds whereincarboxamide is --C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl).

In another subclass of this class of the invention are compounds whereinR¹ is CH₃, R² is selected from H and CH₃, and A¹ is a selected from:carboxamide, including substituted and unsubstituted anilidederivatives, and C₁₋₁₀ alkyl. Further illustrating this subclass arecompounds wherein carboxamide is --C(═O)NH--C₆ H₅ or--C(═O)NH-(2,5-trifluoromethylphenyl) and C₁₋₁₀ alkyl is selected fromisopropyl, isobutyl, 1,5-dimethylhexyl, and 5-methylhexyl.

In another class of the compounds of this embodiment are compoundswherein Z is ##STR10##

Exemplifying compounds of this class are:

(1) N-t-Butyl-4-thia-5α-androst-1-en-3-one-16β-carboxamide,

(2) 16β-(1,5-dimethylhexyl)-7β-Methyl-4-thia-5α-androst-1-en-3-one,

(3)16β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,

(4) 16β-(N-tert-amylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(5) 16β-(N-tert-hexylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(6) 16β-(N-isobutylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(7) 16β-(N-tert-octylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(8) 16β-(N-1,1-diethylbutylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(9) 16β-(N-neopentylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(10) 16β-(N-2-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(11) 16β-(N-1-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(12) 16β-(N-2-norbomylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(13) 16β-(N-1-norbomylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(14) 16β-(N-phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(15) 16β-(N-benzylcarbamoyl)-4-thia-5α-androst-1-en-3-one,

(16)16β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(17)16β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(18)16β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(19)16β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,

(20)16β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,

(21)16β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,

(22) 16β-(N-n-octylcarbamoyl)-4-methyl-4-thia-5α-androst-1-en-3-one,

(23) 16β-(1-methoxyethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(24) 16β-(isopropyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(25) 16β-(4-methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(26)16β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(27)16β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(28) 16β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

(29) 16β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, and

(30)16β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one.

Further exemplifying the compounds of this class are:

16β-(4-methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

16β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,

16β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,

16β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, and

16β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one.

In one subclass of this class, R¹ is C₁₋₅ alkyl, R² is selected fromhydrogen and methyl, and A² is selected from: alkoxy, aryloxy, eitherunsubstituted or substituted, heteroaryloxy, either substituted orunsubstituted, and alkyl, either unsubstituted or substituted.

Further illustrating this subclass are compounds wherein, A² is selectedfrom: substituted aryloxy, and heteroaryloxy, either substituted orunsubstituted.

Exemplifying compounds of this subclass are compounds wherein the C5-C6bond designated with a dotted line is a single bond, and H_(a) ispresent and represents hydrogen.

Further exemplifying the compounds of this subclass are compoundswherein the C5-C6 bond designated with a dotted line is a double bond,and H_(a) is absent.

In another subclass of this class, R¹ is H or CH₃, R² is selected from Hand CH₃, and A² is selected from: substituted and unsubstituted aryl orheteroaryl ether. Further illustrating this subclass are the compoundswherein substituted and unsubstituted aryl or heteroaryl ether isselected from thiophenoxy, biphenyloxy, acetamidophenoxy,(3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy,hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy. Stillfurther illustrating the compounds of the present invention arecompounds wherein substituted or unsubstituted aryl or heteroaryl etheris selected from 4-methyl-phenoxy, 4-chlorophenoxy, and2-pyrimidinyloxy.

In one subclass of this class, R¹ is C₁₋₅ alkyl, R² is selected fromhydrogen and methyl, and A² is selected from: alkoxy, aryloxy, eitherunsubstituted or substituted, heteroaryloxy, either substituted orunsubstituted, and alkyl, either unsubstituted or substituted.

Further illustrating this subclass are compounds wherein, A² is selectedfrom: substituted aryloxy, and heteroaryloxy, either substituted orunsubstituted.

Exemplifying compounds of this subclass are compounds wherein the C5-C6bond designated with a dotted line is a single bond, and H_(a) ispresent and represents hydrogen.

Further exemplifying the compounds of this subclass are compoundswherein the C5-C6 bond designated with a dotted line is a double bond,and H_(a) is absent.

When any variable (e.g., aryl, heterocycle, R¹, etc.) occurs more thanone time in any constituent or in formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

As used herein "alkyl" is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl,butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl,and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu),secbutyl (s-Bu), tertbutyl (t-Bu), isopentane, isohexane, etc."Alkyloxy" (or "alkoxy") represents an alkyl group having the indicatednumber of carbon atoms attached through an oxygen bridge, e.g., methoxy,ethoxy, propyloxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy,t-butoxy and the like.

The term "aryl" includes phenyl and naphthyl. Preferably, aryl isphenyl.

Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl,pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl andbenzofuranyl.

Heterocyclic rings may be attached to structural formula I at anyheteroatom (N, O or S) or carbon atom in the ring which results in thecreation of a stable, uncharged structure.

Hydroxy and amino protecting groups are known to those of ordinary skillin the art, and any such groups may be used. For example, acetate,benzoate, ether and silyl protecting groups are suitable hydroxyprotecting groups. Standard silyl protecting groups have the generalformula --Si(Xa)₃, wherein each Xa group is independently an alkyl oraryl group, and include, e.g. trimethylsilyl, tri-ethylsilyl,tri-i-propylsilyl, triphenylsilyl as well as t-butyl-di-(Xb)-silyl whereXb is methyl, ethyl, i-propyl or phenyl (Ph). Standard amino protectinggroups have the general formula --C(O)--Xc, wherein Xc is alkyl, aryl,O-alkyl or O-aryl, and include, e.g. N-t-butoxycarbonyl. See alsoProtective Groups in Organic Synthesis, T. W. Green et al. (John Wileyand Sons, 1991) for descriptions of protecting groups.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term "pharmaceuticallyacceptable salt" is intended to include all acceptable salts such asacetate, lactobionate, benzenesulfonate, laurate, benzoate, malate,bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate,borate, methylbromide, bromide, methylnitrate, calcium edetate,methylsulfate, camsylate, mucate, carbonate, napsylate, chloride,nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt,dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate(embonate), estolate, palmitate, esylate, pantothenate, fumarate,phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,salicylate, glutamate, stearate, glycollylarsanilate, sulfate,hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,tosylate, isothionate, triethiodide, lactate, panoate, valerate, and thelike which can be used as a dosage form for modifying the solubility orhydrolysis characteristics or can be used in sustained release orpro-drug formulations. Depending on the particular functionality of thecompound of the present invention, pharmaceutically acceptable salts ofthe compounds of this invention include those formed from cations suchas sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, andfrom bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,arginine, ornithine, choline, N,N'-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, andtetramethylammonium hydroxide. These salts may be prepared by standardprocedures, e.g. by reacting a free acid with a suitable organic orinorganic base.

Also, in the case of an acid (--COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed, e.g. methyl, ethyl,butyl, acetate, maleate, pivaloyloxymethyl, and the like, and thoseesters known in the art for modifying solubility or hydrolysischaracteristics for use as sustained release or prodrug formulations.

The compounds of the present invention may have chiral centers otherthan those centers whose stereochemistry is depicted in formula I, andtherefore may occur as racemates, racemic mixtures and as individualenantiomers or diastereomers, with all such isomeric forms beingincluded in the present invention as well as mixtures thereof.Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

The term "therapeutically effective amount" is that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disorder being treated.

More particularly, the present invention relates to a method fortreating hyperandrogenic conditions in a mammal in need of suchtreatment comprising the administration to the mammal in need of suchtreatment of a therapeutically effective amount of a compound of thepresent invention. The novel methods of treatment of this invention arefor disorders known to those skilled in the art. The term "mammal"includes humans. Preferably, the method of the present invention is fortreating hyperandrogenic conditions in a human in need of suchtreatment.

Hyperandrogenic conditions treatable by the method of the presentinvention include benign prostatic hyperplasia, androgenic alopecia(including male pattern baldness, female pattern baldness and femalehirsutism), acne vulgaris, seborrhea, prostatitis and prostaticcarcinoma.

The present invention has the objective of providing methods of treatinghyperandrogenic conditions including androgenic alopecia, male patternbaldness, acne vulgaris, seborrhea, and female hirsutism by oral,systemic, parenteral or topical administration of the novel compounds offormula I either alone or in combination with a 5α-reductase 2inhibitor, preferably selected from finasteride and epristeride, or apotassium channel opener, or a retinoic acid or derivative thereof.Alternatively, treatment may encompass administration of a combinationof a compound of formula I with a 5α-reductase 2 inhibitor, preferablyselected from finasteride and epristeride and another active agent suchas a potassium channel opener, or a retinoic acid or derivative thereof.The term "treating androgenic alopecia" is intended to include thearresting and/or reversing of androgenic alopecia, and the promotion ofhair growth.

The present invention has the further objective of providing methods oftreating benign prostatic hyperplasia, prostatitis, and treating and/orpreventing prostatic carcinoma by oral, systemic or parenteraladministration of the novel compounds of formula I either alone or incombination with a 5α-reductase 2 inhibitor, preferably selected fromfinasteride and epristeride. Alternatively, treatment may encompassadministration of a combination of a compound of formula I with a5α-reductase 2 inhibitor and/or another active agent such as an α1 or anα1_(a) adrenergic receptor antagonist (α1_(a) receptor antagonists wereformerly called α1_(c) receptor antagonists).

The present invention also has a further objective of providing methodsof treating acne vulgaris, androgenic alopecia, seborrhea, femalehirsutism, benign prostatic hyperplasia, prostatitis and the preventingand/or treating of prostatic cancer, by oral, systemic, parental ortopical administration of a combined therapy of a therapeuticallyeffective amount of a compound of formula I with a therapeuticallyeffective amount of an anti-androgen, such as, e.g., flutamide,spironolactone or casodex.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents canbe administered concomitantly, or they each can be administered atseparately staggered times.

The present invention also has the objective of providing suitabletopical, oral, systemic and parenteral pharmaceutical formulations foruse in the novel methods of treatment of the present invention. Thecompositions containing the present compounds as the active ingredientfor use in the treatment of the above-noted conditions can beadministered in a wide variety of therapeutic dosage forms inconventional vehicles for systemic administration. For example, thecompounds can be administered in such oral dosage forms as tablets,capsules (each including timed release and sustained releaseformulations), pills, powders, granules, elixirs, tinctures, solutions,suspensions, syrups and emulsions, or by injection. Likewise, they mayalso be administered in intravenous (both bolus and infusion),intraperitoneal, subcutaneous, topical with or without occlusion, orintramuscular form, all using forms well known to those of ordinaryskill in the pharmaceutical arts. An effective but non-toxic amount ofthe compound desired can be employed as an antiandrogenic agent.

The compounds of structural formula I useful in the present inventionare typically administered in admixture with suitable pharmaceuticaldiluents, excipients or carriers (collectively referred to herein as"carrier" materials) suitably selected with respect to the intended formof administration, that is, oral tablets, capsules, elixirs, syrups andthe like, and consistent with conventional pharmaceutical practices maybe administered systemically, by oral administration or by intravenousor intramuscular injection or topically.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Capsules containing the product of thisinvention can be prepared by mixing an active compound of the presentinvention with lactose and magnesium stearate, calcium stearate, starch,talc, or other carriers, and placing the mixture in gelatin capsules.

Tablets may be prepared by mixing the active ingredient withconventional tableting ingredients such as calcium phosphate, lactose,corn starch or magnesium stearate. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. Other dispersing agents which may beemployed include glycerin and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

Topical pharmaceutical compositions may be, e.g., in the form of asolution, cream, ointment, gel, lotion, shampoo or aerosol formulationadapted for application to the skin. Topical pharmaceutical compositionsuseful in the method of treatment of the present invention may includeabout 0.001% to 0.1% of the active compound in admixture with apharmaceutically acceptable carrier.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, propylene glycol, PPG2 myristyl propionate, and thelike, to form, e.g., alcoholic solutions, topical cleansers, cleansingcreams, skin gels, skin lotions, and shampoos in cream or gelformulations. See, e.g., EP 0 285 382.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen. Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter, arrest or reverse the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy without toxicity requires a regimen basedon the kinetics of the drug's availability to target sites. Thisinvolves a consideration of the distribution, equilibrium, andelimination of a drug. Preferably, doses of the compound of structuralformula I useful in the method of the present invention range from 0.01to 1000 mg per adult human per day. Most preferably, dosages range from0.1 to 50 mg/day. For oral administration, the compositions arepreferably provided in the form of tablets containing 0.01 to 1000milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. An effective amount of the drug is ordinarily supplied ata dosage level of from about 0.0002 mg/kg to about 50 mg/kg of bodyweight per day. The range is more particularly from about 0.001 mg/kg to1 mg/kg of body weight per day.

Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four times daily.

The compounds of the present invention may be used in the preparation ofa medicament useful for the treatment of hyperandrogenic disordersincluding: acne vulgaris, androgenic alopecia, male pattern baldness,seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitisand prostatic cancer.

For the treatment of acne vulgaris, androgenic alopecia, male patternbaldness, seborrhea, female hirsutism, benign prostatic hyperplasia,prostatitis and the prevention and/or treatment of prostatic cancer, thecompounds of the instant invention can be combined with atherapeutically effective amount of another 5α-reductase inhibitor, suchas finasteride or epristeride, or other 5α-reductase inhibitor compoundshaving type 2 activity, type 1 activity or dual activity for bothisozymes, in a single oral, systemic, or parenteral pharmaceuticaldosage formulation. Alternatively, a combined therapy can be employedwherein the compound of formula I and the other 5α-reductase inhibitorare administered in separate oral, systemic, or parenteral dosageformulations. Also, for the skin and scalp related disorders of acnevulgaris, androgenic alopecia, male pattern baldness, seborrhea, andfemale hirsutism, the compounds of the instant invention and another5α-reductase inhibitor such as finasteride or epristeride can beformulated for topical administration. For example, a compound offormula I and finasteride can be administered in a single oral ortopical dosage formulation, or each active agent can be administered ina separate dosage formulation, e.g., in separate oral dosageformulations, or an oral dosage formulation of finasteride incombination with a topical dosage formulation of a compound of formulaI. See, e.g., U.S. Pat. Nos. 4,377,584 and 4,760,071 which describedosages and formulations for 5α-reductase inhibitors.

Furthermore, administration of a compound of the present invention incombination with a therapeutically effective amount of a potassiumchannel opener, such as minoxidil, cromakalin, pinacidil, a compoundselected from the classes of S-triazine, thiane-1-oxide, benzopyran, andpyridinopyran derivatives or a pharmaceutically acceptable salt thereof,may be used for the treatment of androgenic alopecia including malepattern baldness. Therapy may further comprise the administration of a5α-reductase type 2 inhibitor such as finasteride or epristeride, or a5α-reductase type 1 inhibitor, or a type 1 and type 2 dual inhibitor, incombination with a compound of the present invention and a potassiumchannel opener such as minoxidil. The active agents can be administeredin a single topical dosage formulation, or each active agent can beadministered in a separate dosage formulation, e.g., in separate topicaldosage formulations, or an oral dosage formulation of a compound offormula I in combination with a topical dosage formulation of, e.g.,minoxidil, or a single oral dosage formulation of a compound of formulaI and another 5α-reductase inhibitor, in combination with a topicaldosage formulation of, e.g., minoxidil. See, e.g., U.S. Pat. Nos.4,596,812, 4,139,619 and WO 92/02225, published Feb. 20, 1992, fordosages and formulations of calcium channel openers.

Furthermore, for the treatment of acne vulgaris, a combined therapy canbe used by administering a therapeutically effective amount of acompound of formula I in combination with a therapeutically effectiveamount of retinoic acid or a derivative thereof, e.g. an ester or amidederivative thereof, such as e.g., tretinoin or isotretinoin. Optionally,this combined therapy for acne vulgaris may further include a5α-reductase type 2 inhibitor such as finasteride or epristeride, or a5α-reductase type 1 inhibitor, or a dual type 1 and type 2 inhibitorycompound.

Also, for the treatment of benign prostatic hyperplasia, a combinedtherapy comprising a administration of a compound of formula I with a5α-reductase type 2 inhibitor, such as e.g., finasteride, and an alpha-1adrenergic receptor antagonist, such as e.g., terazosin, doxazosin,prazosin, bunazosin, indoramin or alfuzosin, may be employed. Moreparticularly, the combined therapy can comprise administering a compoundof formula I with a 5α-reductase type 2 inhibitor, such as e.g.,finasteride, and an alpha-1_(a) adrenergic receptor antagonist (formerlycalled an alpha-1_(c) adrenergic receptor antagonist). Compounds whichare useful as alpha-1_(a) adrenergic receptor antagonists can beidentified according to procedures known to those of ordinary skill inthe art, for example, as described in PCT/US93/09187 (WO94/08040,published Apr. 14, 1994); PCT/US94/03852 (WO 94/22829, published Oct.13, 1994); PCT/US94/10162 (WO 95/07075, published Mar. 16, 1995), andU.S. Pat. No. 5,403,847.

Also, for the treatment of acne vulgaris, androgenic alopecia,seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitisand the prevention and/or treatment of prostatic cancer, a combinedtherapy can be used by administering a therapeutically effective amountof a compound of formula I with a therapeutically effective amount of ananti-androgen, such as, e.g., flutamide, spironolactone or casodex.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents canbe administered concurrently, or they each can be administered atseparately staggered times.

The compounds of the present invention can be prepared readily accordingto the following Schemes and Examples or modifications thereof usingreadily available starting materials, reagents and conventionalsynthesis procedures. In these reactions, it is also possible to makeuse of variants which are themselves known to those of ordinary skill inthis art, but are not mentioned in greater detail.

The 4-oxa compounds of this invention can be prepared as shown inScheme 1. ##STR11##

Scheme 1 outlines the synthesis of the novel oxasteroids of the presentinvention. The appropriately substituted seco-acid may be prepared bymethods known in the art. PCT publication WO 95/11254 describesprocedures for the synthesis of compounds having various substituents atthe 16-position of the azasteroid. Starting with a 3-keto-delta4-17-oneprecursor and following the procedures of WO 95/11254, the appropriateA² substitution may be obtained. To obtain the appropriate A¹substitution, the procedures of the following publications are followedstarting with a 3-keto-delta4-17-one precursor: for ether or thioetherWO 93/23040; for anilide WO 94/07861, EP 0 663 924; for unsubstituted,monosubstituted or disubstituted amides WO 93/23038, WO 93/23051, WO93/23420; and U.S. Pat. Nos. 4,220,775, 4,760,071, 4,845,104, 5,237,067,5,091,380, 5,061,801, 5,215,894, for oxo U.S. Pat. Nos. 4,220,775,4,377,584; for cyano U.S. Pat. No. 4,220,775; for tetrazoyl U.S. Pat.No. 4,220,775; for arylalkylcarbonlyoxy alkyl U.S. Pat. No. 4,377,584;for cycloalkylarylcarbonlyoxy alkyl U.S. Pat. No. 4,377,584; forbenzoyloxyalkyl U.S. Pat. No. 4,377,584; for acyl, both substituted andunsubstituted, U.S. Pat. No. 5,049,562, U.S. Pat. No. 5,138,063, U.S.Pat. No. 5,151,429, U.S. Pat. No. 5,237,061, U.S. Pat. No. 5,120,742,U.S. Pat. No. 5,162,332, U.S. Pat. No. 5,061,802, U.S. Pat. No.5,098,908, U.S. Pat. No. 5,196,411, U.S. Pat. No. 5,075,450, U.S. Pat.No. 5,061,803, U.S. Pat. No. 5,324,734; for thiobenzyl U.S. Pat. No.5,151,430; for polyaroyl U.S. Pat. No. 5,162,322; for ester U.S. Pat.No. 5,091,534, WO 93/23041, WO 93/23040, for alkyl, either substitutedor unsubstituted WO 93/23050, WO 93/23419, WO 93/23051; for urea,thiourea, carbamate or thiocarbamate WO93/23048; for thioester WO93/23041, WO 93/23040.

The appropriately 7,10,16, and 17-substituted 3-keto steroid isconverted to the appropriately substituted seco-acid by methods known inthe art, for example, the procedures described in Rasmusson, et al.,J.Med.Chem. 1986, 29(11): 2298-2315.

The appropriate 7-β substitution may be obtained following theprocedures for formation of a 7-β bond as described in U.S. Pat. Nos.4,220,775, and 5,237,064.

Compounds wherein R² is H or CH₂ OR³ may be prepared starting with theappropriately C10 substituted seco-acid. These compounds may be made byprocedures known in the art.

As shown in Scheme 1, the seco-acid (1) is treated with a dehydratingagent such as acetic anhydride, methyl ortho-formate, ethylortho-formate, in a nonpolar aprotic solvent such as toluene, xylene,dichloroethane, chlorobenzene and the like optionally in the presence ofan acidic catalyst, such as PTSA (paratoluenesulfonic acid), or sodiumacetate to form the Δ⁵ -oxasteroid (2). Preferably, the seco-acid (1) istreated with acetic anhydride in acetic anhydride in the presence ofsodium acetate at an elevated temperature, preferably at about 140° C.Hydrogenation of the double bond to form the oxasteroid (3) may becarried out in the presence of an appropriate catalyst such as Rh/C,Pd/C, etc., preferably Rh/C in a solvent such as tetrahydrofuran (THF)or ethyl acetate. This is followed by formation of the Δ¹ double bond bytreatment with, for example, dichloro-dicyanoquinone (DDQ),benzeneselenic anhydride in chlorobenzene, or other known methods, forexample as described in U.S. Pat. Nos. 5,084,574 and 5,021,571, to formthe Δ¹ -oxasteroid (4).

The 4-thia compounds of this invention can be prepared as shown inScheme 2. ##STR12##

Starting with the 4-oxa-androstan-3-one appropriately substituted in theB and D-ring, obtained by following the procedures of Scheme 1 to obtaincompound (3), the lactone is opened to form the hydroxamide (5). Thelactone may be opened by various means such as treatment withdimethylalumino-3-aminopyridine (which may be prepared in situ bytreating trimethyl aluminum with 3-amino pyridine), chlorobenzene ordichloroethane in a nonpolar, aprotic solvent such as toluene.

The hydroxamide (5) is treated with alkyl- or aryl sulfonyl chloride ina solvent such as methylene chloride, toluene or dichloroethane in thepresence of a base such as pyridine, dimethylaminopyridine (DMAP), orN-methylpyrolidine (NMP), to give the corresponding alkyl- or arylsulfonate (6). The reaction of the alkyl- or aryl sulfonate withtetrabutylammonium iodide in a polar aprotic solvent such as tolueneproduces the corresponding iodide (7). The iodide is treated withthioacetic acid in a nonpolar solvent such as toluene or dichloroethanein the presence of cesium carbonate or other base such as potassiumcarbonate or sodium carbonate to give the thioacetate (8). Thethioacetate (8) is hydrolyzed to form the thialactone (9), preferably bytreatment with acid in a polar solvent such as methanol or ethanol,preferably by treatment with hydrochloric acid in methanol. Thethialactone (9) may be dehydrogenated to form the Δ¹ -thiasteroid (10)as described above, preferably by treatment with benzeneselenicanhydride in chlorobenzene at reflux.

The 4-oxa and 4-thia steroids of the present invention include the1,2-5,6 diene which may be prepared by treating the compound ofstructural formula (2) with benzeneselenic anhydride in chlorobenzenewith refluxing to obtain the Δ¹,Δ⁵ -oxasteroid derivative. Thecorresponding thiasteroid derivative may be obtained by following theprocedures of Scheme 2, starting with (2), the Δ⁵ -oxasteroid.

The following examples are not intended to be limitations on the scopeof the instant invention in any way, and they should not be soconstrued. Furthermore, the compounds described in the followingexamples are not to be construed as forming the only genus that isconsidered as the invention, and any combination of the compounds ortheir moieties may itself form a genus. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds.

All temperatures given in the following examples are in degrees Celsius.¹ H and ¹³ C nuclear magnetic resonance (NMR) spectra were taken at 400or 500 MHz at ambient temperature in the solvents indicated. Someabbreviations used herein are as follows: "BOC" is t-butoxycarbonyl;"BOC anhydride" is di-t-butyl dicarbonate {O(CO₂ C(CH₃)₃)₂ }; "DBU" is1,8-diaza-bicyclo[5.4,0]undec-7-ene; "DCC" is1,3-dicyclohexylcarbodiimide; "DMS" is methyl sulfide {(CH₃)₂ S}; "DMF"is dimethylformamide; "EtOAc" is ethyl acetate; "HOBT" is1-hydroxybenzotriazole; "IPA" is isopropyl acetate; "Ph" is phenyl; "Tf"is --SO₂ CF₃ ; "TFA" is trifluoroacetic acid; "THF" is tetrahydrofuran;"TIPS" is triisopropylsilyl; "TIPSO" is triisopropylsilyloxy. Unlessotherwise specified "tlc" and "TLC" refer to thin layer SiO₂chromatography.

EXAMPLE 1 Preparation ofN-t-Butyl-4-oxa-5α-androst-1-en-3-one-17β-carboxamide

Step 1: Benzotriazol-1'-yl-3-oxo-androst-4-ene-17β-carboxamide ##STR13##

To a solution of steroid acid (4 g, 12.65 mmol, see Rasmusson et al.,J.Med.Chem. 1986, 29(11): 2298-2315 for description of synthesis) inmethylene chloride was added DCC (2.75 g, 13.3 mmol) and1-hydroxybenzotriazole (HOBT, 2.75 g, 19.1 mmol). After stirring thereaction mixture for overnight, the solid was filtered, dried and usedas such for further reactions.

Step 2: N-t-Butyl-3-oxo-androst-4-ene-17β-carboxamide ##STR14##

To a solution of benzotriazol-1'-yl-3-oxo-androst-4-ene-17β-carboxamide(1.5 g, 3.46 mmol) in methylene chloride was added t-butyl amine (454μl,4.33 mmol). After stirring the reaction mixture for overnight, thereaction mixture was concentrated, purified by chromatography oversilica gel (2.5% acetone/methylene chloride). Mass spec. M⁺ 372(m+1,observed).

Step 3: N-t-Butyl-5-oxo-3,5-secoandrostan-3-oic-17β-carboxamide##STR15##

To a solution of N-t-butyl-3-oxo-androst-4-ene-17β-carboxamide (550 mg,1.48 mmol) in t-butanol (10 mL) was added sodium carbonate (172 mg, 1.63mmol, in 1 mL of H₂ O). The reaction mixture was heated to 80° and asolution of NaIO₄ (1.58 g, 7.4 mmol) and KMnO₄ (11.7 mg, 0.074 mmol) inH₂ O (10 mL) was added dropwise in ˜10 minutes. After stirring thereaction mixture for 2 hrs, the mixture was cooled to room temperatureand acidified to pH 2. The reaction mixture was concentrated, extractedwith ethyl acetate, organic layer was dried and concentrated to givepure product. Mass spec. M⁺ 392(m+1, observed).

Step 4: N-t-Butyl-4-oxa-androst-5-en-3-one-17β-carboxamide ##STR16##

To a solution of N-t-butyl-5-oxo-3,5-secoandrostan-3-oic-17β-carboxamide(550 mg, 1.4 mmol) in acetic anhydride (25 mL) was added sodium acetate(1.91 g, 14 mmol). After stirring the reaction mixture at refluxtemperature for 4 hrs, the acetic anhydride was removed under vacuum andresidue partitioned between ethyl acetate and water. The organic layerwas washed with brine, dried, concentrated and purified by prep. tlc (5%acetone/methylene chloride). Mass spec. M⁺ 374(m+1, observed).

Step 5: N-t-Butyl-4-oxa-5α-androstan-3-one-17β-carboxamide ##STR17##

To a solution of N-t-butyl-4-oxa-androst-5-en-3-one-17β-carboxamide (410mg, 1.099 mmol) in THF (20 mL) was added 5% Rh/C(410 mg). After stirringthe reaction mixture under H₂ atmosphere for overnight, the mixture wasflushed with N₂, filtered and concentrated. The residue was purified byprep. tlc (5% acetone/CH₂ Cl₂). Mass spec. M⁺ 376(m+1, observed).

Step 6: N-t-Butyl-4-oxa-5α-androst-1-en-3-one-17β-carboxamide ##STR18##

To a solution of N-t-butyl-4-oxa-5α-androstan-3-one-17β-carboxamide (100mg, 0.27 mmol) in chlorobenzene was added benzeneselenic anhydride (177mg, 0.49 mmol). After stirring the reaction mixture at refluxtemperature for overnight, the reaction mixture was diluted with ethylacetate, washed with brine, dried and concentrated. The residue waspurified by prep. tlc (5% acetone/CH₂ Cl₂). Mass spec. M⁺ 374(m+1,observed).

EXAMPLE 2 Preparation of 7β-Methyl-4-oxa-5α-Cholest-1-en-3-one ##STR19##Step 1: 7β-Methyl-4-oxa-Cholest-5-en-3-one

To a solution of 7β-methyl-5-oxo-3,5-secocholestan-3-oic (5 g, 12.3mmol) in acetic anhydride (250 mL) was added sodium acetate (16.9 g, 124mmol). After stirring the reaction mixture at reflux temperature for 4hrs, the acetic anhydride was removed under vacuum and residuepartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried, concentrated and purified by chromatographyover silica gel. Mass spec. M⁺ 401(m+1, observed).

Step 2: 7β-Methyl-4-oxa-5α-Cholestan-3-one ##STR20##

To a solution of 7β-methyl-4-oxa-Cholest-5-en-3-one (6.0 g) in THF (50mL) was added 5% Rh/C(6.5 g). After stirring the reaction mixture underH₂ atmosphere for overnight, the mixture was flushed with N₂, filteredand concentrated. The residue was purified by chromatography over silicagel (20% ethyl acetate/hexane). Mass spec. M⁺ 403(m+1, observed).

Step 3: 7β-Methyl-4-oxa-5α-Cholest-1-en-3-one ##STR21##

To a solution of 7β-methyl-4-oxa-5α-Cholestan-3-one (1 g, 2.49 mmol) inchlorobenzene (50 mL) was added benzeneseleninic anhydride (1.165 g,3.24 mmol). After stirring the reaction mixture at reflux temperaturefor overnight, the reaction mixture was diluted with ethyl acetate,washed with brine, dried and concentrated. The residue was purified bychromatography over silica gel (10% ethyl acetate/hexane). Mass spec. M⁺401(m+1, observed).

EXAMPLE 3 Preparation ofN-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-1-en-3-one-17β-carboxamide

Step 1: S-2'-Pyridyl-3-oxo-androst-4-ene-17β-thiocarboxylate ##STR22##

To a solution of steroid acid (10.26 g, 30 mmol) in toluene (50 mL) wasadded Aldrithiol (15.97 g, 72.49 mmol) and triphenylphosphine (16.88 g,72.49 mmol). After stirring the reaction mixture for overnight at 23°,the reaction mixture was concentrated and purified by chromatographyover silica gel using methylene chloride as solvent.

Step 2:N-(2',5'-Bistrifluoromethylphenyl)-3-oxo-androst-4-ene-17β-carboxamide##STR23##

To a solution of S-2'-pyridyl-3-oxo-androst-4-ene-17β-thiocarboxylate(2.179 g, 5.19 mmol) in methylene chloride was added2,5-bistrifluoromethylaniline (3 g, 13 mmol) and silver triflate (1.336g, 5.2 mmol). After stirring the reaction mixture for overnight at 23°,the mixture was filtered, concentrated and purified by chromatographyover silica gel using methylene chloride as solvent to give pureproduct.

Step 3:N-(2',5'-Bistrifluoromethylphenyl)-5-oxo-3,5-secoandrostan-3-oic-17β-carboxamide##STR24##

To a solution ofN-(2',5'-Bistrifluoromethylphenyl)-3-oxo-androst-4-ene-17β-carboxamide(600mg, 1.27 mmol) in t-butanol (10 mL) was added sodium carbonate (200 mg,1.88 mmol, in 1 mL of H₂ O). The reaction mixture was heated to 80° anda solution of NaIO₄ (1.81 g, 8.5 mmol) and KMnO₄ (13.2 mg, 0.08 mmol) inH₂ O (10 mL) was added dropwise in ˜10 minutes. After stirring thereaction mixture for 2 hrs, the mixture was cooled to room temperatureand acidified to pH 2. The reaction mixture was concentrated, extractedwith ethyl acetate, organic layer was dried and concentrated to givepure product

Step 4:N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one-17β-carboxamide##STR25##

To a solution ofN-(2',5'-bistrifluoromethylphenyl)-5-oxo-3,5-secoandrostan-3-oic-17β-carboxamide(600 mg, 1.19 mmol) in acetic anhydride (10 mL) was added sodium acetate(1.63 g, 11.9 mmol). After stirring the reaction mixture at refluxtemperature for 4 hrs, the acetic anhydride was removed under vacuum andresidue partitioned between ethyl acetate and water. The organic layerwas washed with brine, dried, concentrated and purified by prep. tlc (5%acetone/methylene chloride). Mass spec. M⁺ 530 (m+1, observed).

Step 5:N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androstan-3-one-17β-carboxamide##STR26##

To a solution ofN-(2',5'-bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one-17β-carboxamide(230 mg, 0.433 mml, prepared according to the procedures of Example 7)in THF (5 mL) was added 5% Rh/C (200 mg). After stirring the reactionmixture for overnight under hydrogen atmosphere, the reaction mixturewas flushed with nitrogen, filtered, concentrated and purified bypreparative tlc (50% EtOAc/hexane) to give pure product. Mass spec. M⁺532 (m+1, observed).

Step 6:N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-1-en-3-one-17β-carboxamide##STR27##

To a solution ofN-(2',5'-bistrifluoromethylphenyl)-4-oxa-androstan-3-one-17β-carboxamide.(35 mg, 0.066 mmol, prepared according to the procedures of Example 8)in chlorobenzene (5 mL) was added benzeneseleninic anhydride (30 mg,0.085 mmol). After stirring the reaction mixture at reflux temperaturefor overnight, the reaction mixture was diluted with ethyl acetate,washed with brine, dried and concentrated. The residue was purified byprep. tlc (50% EtOAc/hexane). Mass spec. M⁺ 530(m+1, observed).

EXAMPLE 4 N-t-Butyl-4-thia-5α-androst-1-en-3-one-17β-carboxamide

Step 1:(N-Pyrid-3-yl)-5-hydroxy-3,5-secoandrostan-3-carboxamide-17β-(N-t-butyl)carboxamide

From 500 mg of the product of step 5 of Example 1[N-(t-butyl)-4-oxa-androstan-3-one-17β-carboxamide], the title compoundis prepared by treatment with 1.25 equivalents of the dimethylaluminumcomplex with 3-aminopyridine by reflux in toluene for 30 min. or untilthe A-ring opening is shown to be complete by hplc or thin-layerchromatography. Purification is optional by column chromatography tofurnish the product in good yield.

Step 2:(N-Pyrid-3-yl)-5-p-toluenesulfonyloxy-3,5-secoandrostan-3-carboxamide-17.beta.-(N-t-butyl)carboxamide

The product of step 1 in pyridine solution (50 mL) is cooled to 5° inice before 1.2 equivalents of p-toluenesulfonyl chloride is added. Afterstanding 18 hours in the refrigerator, the reaction is warmed to ambienttemperature, partitioned between water and dichloromethane and washedwith dilute bicarbonate solution to remove residual sulfonyl chloride.The organic layer is dried and evaporated to a residue, which isimmediately taken on to the iodide displacement.

Step 3:(N-Pyrid-3-yl)-5-(epi)iodo-3,5-secoandrostan-3-carboxamide-17β-(N-t-butyl)carboxamide

The tosyl derivative of step 2 is stirred at ambient temperature with 3equivalents of dry tetrabutylammonium iodide in toluene for 30 min. andthen heated at reflux for another 2 hrs. The reaction mixture is cooled,partitioned with dichloromethane and water, and washed to removeammonium salts. After drying and solvent removal under reduced pressure,the residual amorphous material is chromatographed to provide the pureiodo compound.

Step 4:(N-Pyrid-3-yl)-5-acetylthio-3,5-secoandrostan-3-carboxamide-17β-(N-t-butyl)carboxamide

The iodo compound of step 3 is stirred at ambient temperature with 10equivalents of thioacetic acid in toluene for 30 min. and then heated atreflux for another 2 hrs. The reaction mixture is cooled, solvents andvolatile reactants evaporated under reduced pressure, and the residualamorphous material chromatographed.

Step 5: N-t-Butyl4-thia-5α-androstan-3-one-17β-carboxamide

The thioacetyl derivative of step 4 is treated at ambient temperaturewith methanolic HCl (3%) until the starting material is gone bythin-layer chromatography or hplc. Product is isolated by chromatographyand recrystallized.

Step 6 N-t-Butyl-4-thia-5α-androst-1-en-3-one-17β-carboxamide

Treatment of the product of step 5 with phenylseleninic anhydride by themethod of step 6 of Example 1 affords the product.

EXAMPLE 5 Oral Composition

As a specific embodiment of an oral composition of a compound of thisinvention, 5 mg of a compound of structural formula I is formulated withsufficient finely divided lactose to provide a total amount of 580 to590 mg to fill a size 0 hard gelatin capsule.

Biological Assays

Preparation of Human Prostatic and Scalp 5α-reductases

Samples of human tissue were pulverized using a freezer mill andhomogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesiumsulfate, 25 mM potassium chloride, 1 mM phenylmethylsulfonyl fluoride, 1mM dithiothreitol (DTT) containing 0.25 M sucrose using aPotter-Elvehjem homogenizer. A crude nuclear pellet was prepared bycentrifugation of the homogenate at 1,500×g for 15 min. The crudenuclear pellet was washed two times and resuspended in two volumes ofbuffer. Glycerol was added to the resuspended pellet to a finalconcentration of 20%. The enzyme suspension was frozen in aliquots at-80° C. The prostatic and scalp reductases were stable for at least 4months when stored under these conditions.

5α-Reductase Assay

The reaction mixture for the type 1 5α-reductase contained 40 mMpotassium phosphate, pH 6.5, 5 mM [7-³ H]-testosterone, 1 mMdithiothreitol and 500 μM NADPH in a final volume of 100 μl. Thereaction mixture for the type 2 5α-reductase contained 40 mM sodiumcitrate, pH 5.5, 0.3 mM [7-³ H]-testosterone, 1 mM dithiothreitol and500 μM NADPH in a final volume of 100 μl. Typically, the assay wasinitiated by the addition of 50-100 μg prostatic homogenate or 75-200 μgscalp homogenate and incubated at 37° C. After 10-50 min. the reactionwas quenched by extraction with 250 μl of a mixture of 70% cyclohexane:30% ethyl acetate containing 10 μg each DHT and T. The aqueous andorganic layers were separated by centrifugation at 14,000 rpm in anEppendorf microfuge. The organic layer was subjected to normal phaseHPLC (10 cm Whatman partisil 5 silica column equilibrated in 1 mL/min70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min.;androstanediol, 7.6-8.0 min.; T, 9.1-9.7 min.). The HPLC systemconsisted of a Waters Model 680 Gradient System equipped with a HitachiModel 65560 autosampler, Applied Biosystems Model 757 variable UVdetector, and a Radiomatic Model A120 radioactivity analyzer. Theconversion of T to DHT was monitored using the radioactivity flowdetector by mixing the HPLC effluent with one volume of Flo Scint 1(Radiomatic). Under the conditions described, the production of DHT waslinear for at least 25 min. The only steroids observed with the humanprostate and scalp preparations were T, DHT and androstanediol.

Inhibition Studies

Compounds were dissolved in 100% ethanol. The compound to be tested waspre-incubated with the enzyme (either 5α-reductase type 1 or 2) prior toinitiation by addition of substrate testosterone. IC₅₀ values representthe concentration of inhibitor required to decrease enzyme conversion oftestosterone to dihydrotestosterone by 50% of the control. IC₅₀ valueswere determined using a 6 point titration where the concentration of theinhibitor was varied from 0.1 to 1000 nM. Representative compounds ofthis invention were tested in the above described assay for 5α-reductasetype 1 and type 2 inhibition.

A compound referred to herein as a 5α-reductase 1 inhibitor is acompound that shows inhibition of the 5α-reductase 1 isozyme in theabove-described assay, having an IC₅₀ value of about or under 100 nM.

A compound referred to herein as a 5α-reductase 2 inhibitor is acompound that shows inhibition of the 5α-reductase 2 isozyme in theabove-described assay, having an IC₅₀ value of about or under 100 nM.

Human Dermal Papilla Cell Assay

The dermal papilla is a small group of cells at the base of each hairfollicle, and it is presently thought that these cells are stem cellsthat form the basis for hair growth. These cells have been shown to have5α reductase activity, and it is therefore possible to test inhibitorsof 5α reductase in these cell culture systems.

Isolated and cultured dermal papilla cells are prepared according to themethods of Messenger, A. G., "The Culture of Dermal Papilla Cells FromHuman Hair Follicles," Br. J. Dermatol., 110:685-689 (1984) and Itami,S. et al., "5α-Reductase Activity In Cultured Human Dermal Papilla CellsFrom Beard Compared With Reticular Dermal Fibroblasts," J. Invest.Dermatol., 94:150-152 (1990). Beard dermal papilla cells and occipitalscalp hair of two different individuals are used throughout the study.All experiments are performed at confluency after the fourth to sixthsubculture. Confluent monolayers are rinsed twice withphosphate-buffered saline, scraped from dishes by rubber policemen, andcollected into a centrifuge tube. The cell suspensions are centrifugedat 1,500 rpm for 10 min. at 4° C. The pellets are resuspended in 20 mMTris-HCl buffer, pH 7.5, at 4° C., containing 250 mM sucrose, 1 mMMgCl₂, and 2 mM CaCl₂, by vortexing and 10 passes through a 25-gaugeneedle. The crude homogenate is further homogenized by a teflon-glasshomogenizer, and is used as the cell homogenate. For the study ofsubcellular localization of 5α-reductase, the cell homogenate iscentrifuged at 800×g for 10 min. to yield a crude nuclear pellet. Theresultant supernatant is centrifuged at 10,000×g for 15 min. to producea crude mitochondrial pellet. The supernatant is centrifuged at100,000×g for 60 min. to yield a microsomal pellet and cytosol. Eachparticulate fraction is washed twice and resuspended in the buffer.

A standard incubation mixture will consist of 50 nM [³ H]-testosterone,1 mM NADPH, 100 mM sodium citrate, pH 5.5 or 100 mM Tris-HCl, pH 7.5,and 50 mL of the cell homogenate, in a final volume of 100 mL. Each tubecontains 50-100 mg of cellular protein. Incubation is carried out at 37°C. for 30 min. During this incubation, the reaction is proportional tothe time. For the study of optimum pH, citrate buffer is used at pH4.5-6.5, and the Tris HCl buffer at pH 7.0-9.0. The protein content isdetermined by the method of Lowry, et al., "Protein Measurement With TheFolin Phenol Reagent," J. Biol. Chem., 193:265-275 (1951).

After incubation, the reaction is stopped by adding 4 times volume ofchloroform-methanol (2/1:V/V) containing 110 mg each of carriersteroids. The extracted steroids are analyzed by thinlayerchromatography as previously described by Gomez, et al., "In VitroMetabolism Of Testosterone-4-¹⁴ C and D-androstene-3, 17-dione-4-¹⁴ C InHuman Skin.," Biochem., 7:24-32 (1968), and the purity of each steroidis determined by the recrystallization method. The activity of5α-reductase is expressed by the sum of dihydrotestosterone,androstanediol and androstanedione formed. [1,2-³ H]-testosterone (55.2Ci/mmol) is obtainable from New England Nuclear Corporation (Boston,Mass.) and unlabeled steroids can be purchased from Sigma ChemicalCompany (St. Louis, Mo.). Fetal calf serum is obtainable from Hazleton(Lenaxa, Kans.). All other chemicals are of reagent grade.

The following describes an example of methodology that can be used fordetection of hair growth.

Macrophotography and Global Photography Procedure for Detection of HairGrowth

A. Macrophotographic Procedure

Location:

ID card

Haircount target area

Equipment:

Film:

Kodak-T-max 24 exposure each of same emulsion lot number

Camera:

Nikon N-6000

Lens:

Nikkor 60 mm f2.8

Flashes:

Nikon SB-21B Macroflash

Device:

registration device

Photographic Procedure

In these clinical photographs, the only variable allowed is thehaircount. Film emulsion, lighting, framing, exposure, and reproductionratios are held constant.

1. The haircount area on the patient is prepared as follows: A small (˜1mm) dot tattoo is placed at the beginning of the study at the leadingedge of the bald area directly anterior to the center of the vertex baldspot, using a commercial tattooing machine or manually (needle and ink).An area approximately one square inch in size, centered at the tattoo atthe leading edge of the balding area, is clipped short (˜2 mm). Cuthairs are removed from the area to be photographed, using tape.Compressed air and/or ethanol wipes may also be used to facilitateremoval of cut hairs.

2.

Magnification:

Each lens supplied has a fixed reproduction ratio of 1:1.2.

Aperture:

Every photograph is taken at f/22.

Film:

T-Max 100 (24 exposure) is used.

3. Patient's haircount target area. Three exposures (-2/3, 0, and +2/3f-stop).

A trained technician places a transparency over the photographic printand, using a felt tip pen, places a black dot over each visible hair.The dot map transparency is then counted using image analysis withcomputer assistance.

Photographs are coded with a random number corresponding to study site,visit number and patient allocation number to insure blinding to time.At Month 6, baseline and Month 6 photographs are counted and dataanalyzed for interim analysis. At Month 12, baseline, Month 6 and Month12 photographs are counted and data analyzed for the primary endpoint.

Methodology for detection of hair growth is also described in Olsen, E.A. and DeLong, E., J. American Academy of Dermatology, Vol. 23, p. 470(1990).

B. Global Photographic Procedure

Locations:

Color card/patient Id

Global photograph

Equipment:

Film:

Kodachrome KR-64 24 exposure each of same emulsion lot number

Camera:

Nikon N-6000

Lens:

Nikkor 60 mm f2.8

Flashes:

Nikon SB-23

Photographic Procedure

In these clinical photographs, the only variable allowed is the globalarea's appearance. Anything extraneous to the area (clothing, furniture,walls, etc.) is eliminated from the fields to be photographed.

1. Patients will have global photographs taken prior to hair clippingwith the head in a fixed position (determined by the suppliedstereotactic device). Hair on the patient's head is positionedconsistently so as to not obscure the bald area.

2. Magnification: Each lens supplied has a fixed reproduction ratio of1:6.

Aperture:

Every photograph will be taken at f/11.

Film:

Kodachrome (24 exposure) is used.

3. Patient's global photographs. Three exposures at zero compensation.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A compound of structural formula (I): ##STR28##or a pharmaceutically acceptable salt, ester or stereoisomer thereof,wherein:the C5-C6 bond designated with a dotted line independentlyrepresents a single or double bond, provided that when the C5-C6 is adouble bond, H_(a) is absent and when the C5-C6 bond is a single bondH_(a) is present and represents hydrogen; X is sulfur; R¹ is selectedfrom hydrogen and C₁₋₅ alkyl; R² is selected from CH₃, CH₂ OR³, and H;R³ is selected from: C₁₋₅ alkyl; Z is ##STR29## A¹ is selected from: (1)--H,(2) keto, (6) carboxy, (7) protected amino, (8) amino, (9)substituted or unsubstituted C₂₋₁₀ alkenyl, (10) aryl-substituted C₁₋₁₀alkyl, (11) aryl or heteroaryl, (12) substituted aryl or heteroaryl,(13) aryl or heteroaryl carbamoyl-substituted C₁₋₁₀ alkyl, (14) aryl orheteroaryl carbonyl, (15) ether-substituted C₁₋₁₀ alkyl, (16)thioether-substituted C₁₋₁₀ alkyl, (17) keto-substituted C₁₋₁₀ alkyl,(18) heteroaryl-substituted C₁₋₁₀ alkyl, (19) carboxylic ester, (20)carboxamide, including substituted and unsubstituted anilidederivatives, (21) urea, (22) C₁₋₁₀ alkylureido C₀₋₅ alkyl, (23)substituted or unsubstituted heteroaryl or arylureidoC₀₋₅ alkyl, (24)C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl, (25) C₁₋₁₀ alkylcarbonylamino, (26)alkanoylamidoalkyl (28) ether, (29) thio ether, and (30) substituted andunsubstituted aryl or heteroaryl ether; A² is selected from:(1) --H, (2)keto, (3) protected hydroxy, (4) acetate, (5) hydroxy, (6) carboxy, (7)protected amino, (8) amino, (9) C₁₋₁₀ alkyl, (10) substituted orunsubstituted C₂₋₁₀ alkenyl, (11) aryl-substituted C₁₋₁₀ alkyl, (12)aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl orheteroaryl carbamoyl-substituted C₁₋₁₀ alkyl, (15) C₁₋₁₀ alkylcarbonyl,(16) aryl or heteroaryl carbonyl, (17) ether-substituted C₁₋₁₀ alkyl,(18) thioether-substituted C₁₋₁₀ alkyl, (19) keto-substituted C₁₋₁₀alkyl, (20) heteroaryl-substituted C₁₋₁₀ alkyl, 21) carboxylic ester,(22) carboxamide, including substituted and unsubstituted anilidederivatives, (23) urea, (24) C₁₋₁₀ alkylureido C₀₋₅ alkyl, (25)substituted or unsubstituted arylureidoC₀₋₅ alkyl, (26) C₁₋₁₀alkanoyloxyC₁₋₂ alkyl, (27) C₁₋₁₀ alkylcarbonylamino, (28)alkanoylamidoalkyl, (29) ether, (30) thio ether, and (31) substitutedand unsubstituted aryl- or heteroaryl-ether; and heteroaryl is selectedfrom: piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl,thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
 2. The compoundof claim 1 wherein:(a) protected hydroxy is selected from:dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy,tri-isopropylsilyloxy, and triphenylsilyloxy; (b) protected amino isacetylamino, benzoylamino, and pivaloylamino; (c) C₁₋₁₀ alkyl isselected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl,6-methylhept-2-yl, and 1-methyl-4-isopropylhexyl; (d) aryl substitutedC₁₋₁₀ alkyl is omegaphenylpropyl; (e) aryl is selected from phenyl, andnaphthyl; (f) substituted aryl or heteroaryl is selected from phenyl,pyridyl and pyrimidinyl substituted with one to three substituentsindependently selected from:(1) --H, (2) --OH, (3) --CH₃, (4) --OCH₃,(5) --S(O)_(n) --CH₃, wherein n is selected from 0, 1, and 2, (6) --CF₃,(7) halo, (8) --CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl,(13) OCH₂ CH₃, (14) OC(CH₃)₃, and (15) --NHR⁷, wherein R⁷ is selectedfrom: --H, --C₁₋₈ alkyl, --C₁₋₆ alkylcarbonyl, --C₁₋₆ alkylsulfonyl, and--C₁₋₆ alkoxycarbonyl, (g) aryl or heteroaryl carbamoyl substitutedC₁₋₁₀ alkyl is 2-(4-pyridyl-carbamoyl)ethyl; (h) C₁₋₁₀ alkylcarbonyl isselected from isobutylcarbonyl and isopropylcarbonyl; (i) aryl orheteroaryl carbonyl is selected from phenylcarbonyl and pyridylcarbonyl; (j) ether-substituted C₁₋₁₀ alkyl is selected from1-methoxy-ethyl and 1-ethoxy-ethyl; (k) thioether-substituted C₁₋₁₀alkyl is selected from 1-methylthio-ethyl, and 1-ethylthio-ethyl; (l)keto-substituted C₁₋₁₀ alkyl is 1-keto-ethyl, ketomethyl, 1-ketopropyl,and ketobutyl; (m) heteroaryl-substituted C₁₋₁₀ alkyl isomega-(4-pyridyl)butyl; (n) carboxylic esters are C₁₋₁₀ alkylcarboxylicesters selected from carbomethoxy and carboethoxy; (o) carboxamides areselected from N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-diphenylmethyl)carboxamide, N-(diphenylmethyl)-carboxamide,N-t-butyl carboxamide, N-isopropyl carboxamide, 1-adamantyl carboxamide,2-adamantyl carboxamide and N-(substituted phenyl)carboxamides whereinthe phenyl may be substituted with 1 to 2 substitutents selected fromethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I); (p) C₁₋₁₀alkanoyloxyC₁₋₂ alkyl is selected from acetyloxymethyl,trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl; (q) urea ist-butylcarbonylamino urea; (r) C₁₋₁₀ alkylureido C₀₋₅ alkyl is selectedfrom: N-t-butylureidomethyl, N-n-propylureidomethyl,N-n-octylureidomethyl and, N-isopropylureido, (s) substituted orunsubstituted arylureidoC₀₋₅ alkyl is selected from:N-(ethylphenyl)ureidomethyl, N-(chlorophenyl)ureidomethyl,N-phenylureidomethyl, N-(dichlorophenyl)ureidomethyl,N-(naphth-2-yl)ureidomethyl, N-(fluorophenyl)ureido,N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl; (t) C₁₋₁₀alkylcarbonylamino is t-butylcarbonylamino; (u) alkanoylamidoalkyl isselected from: trimethylacetamidomethyl,carbomethoxyoctanoylamidomethyl, (isobutylphenyl)propionamidomethyl,8-carboxyoctanoylamidomethyl, bromoheaxanoylamido methyl,hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl,isopropylthioacetamidomethyl, benzyloxyacetamidomethyl,carbomethoxyacetamidomethyl, triphenylproprionamidomethyl,cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl,(3-hydroxy-4,4,4-trichlorobutyramido)methyl, andphenylthioacetamidomethyl; (u) ether is C₁₋₈ alkyl ether optionallysubstituted with hydroxy, halo, C₁₋₈ alkoxy, C₂₋₆ alkenyl, or aryl; (w)thioether is selected from: C₁₋₈ alkylthio, phenylthio, and C₁₋₈alkylthio substituted with phenyl; and (x) substituted and unsubstitutedaryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy,acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy,phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.3. The compound of claim 1 wherein Z is:Z is ##STR30##
 4. The compoundof claim 3 wherein: R¹ is hydrogen, R² is selected from H and CH₃, andA¹ is carboxamide.
 5. The compound of claim 4 wherein carboxamide isselected from:N,N-diisopropyl carboxamide, N-t-butyl carboxamide,N-t-octyl carboxamide, N-n-octyl carboxamide,N-(hydroxyphenyl)carboxamide, N-phenylcarboxamide,N-(aminophenyl)carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy)phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-diphenylmethyl)carboxamide, N-(diphenylmethyl)-carboxamide,N-t-butyl carboxamide, N-isopropyl carboxamide, 1-adamantyl carboxamide,2-adamantyl carboxamide, and N-(substituted phenyl)carboxamides,wherein:the phenyl may be substituted with 1 to 2 substitutents selectedfrom ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
 6. Thecompound of claim 5 wherein carboxamide is selected from:--C(═O)NH--C(CH₃)₃, --C(═O)NH--C₆ H₅ and--C(═O)NH--(2,5-trifluoromethylphenyl).
 7. The compound of claim 3,wherein:R¹ is CH₃, R² is selected from H and CH₃, and A¹ is carboxamide.8. The compound of claim 7 wherein carboxamide is selected from--C(═O)NH--C₆ H₅ and --C(═O)NH-(2,5-trifluoromethylphenyl).
 9. Thecompound of claim 1 wherein Z is ##STR31##10.
 10. The compound of claim9 wherein R¹ is H or CH₃, R² is selected from H and CH₃, and A² isselected from: aryl ether and heteroaryl ether, either unsubstituted orsubstituted with one to three substituents independently selected from:(1) --H,(2) --OH, (3) --CH₃, (4) --OCH₃, (5) --S(O)_(n) --CH₃, wherein nis selected from 0, 1, and 2, (6) --CF₃, (7) halo, (8) --CHO, (9) CN,(10) phenyloxy, (11) ethyl, (12) t-butyl, (13) OCH₂ CH₃, (14) OC(CH₃)₃,and (15) --NHR⁷, wherein R⁷ is selected from: --H, --C₁₋₈ alkyl, --C₁₋₆alkylcarbonyl, --C₁₋₆ alkylsulfonyl, and --C₁₋₆ alkoxycarbonyl.
 11. Thecompound of claim 10 wherein substituted and unsubstituted aryl orheteroaryl ether is selected from thiophenoxy, biphenyloxy,acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy,phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.12. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 1. 13. The compound selected from:(1)N-t-Butyl-4-thia-5α-androst-1-en-3-one-17β-carboxamide, (2)7β-Methyl-4-thia-5α-cholest-1-en-3-one, (3)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,(4)17β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,(5)17β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,(6)17β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one,(7) 17β-(N-tert-amylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (8)17β-(N-tert-hexylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (9)17β-(N-isobutylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (10)17β-(N-tert-octylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (11)17β-(N-1,1-diethylbutylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (12)17β-(N-neopentylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (13)17β-(N-2-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (14)17β-(N-1-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (15)17β-(N-2-norbornylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (16)17β-(N-1-norbornylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (17)17β-(N-phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (18)17β-(N-benzylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (19)17β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(20) 17β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one, (21)17β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(22) 17β-(N-n-octylcarbamoyl)-4-methyl-4-thia-5α-androst-1-en-3-one,(23) 17β-(1-methoxyethyl)-7β-methyl-4-thia-5α-androst-1-en-3one (24)17β-(isopropyl)-7β-methyl-4-thia-5α-androst-1-en-3-one, (25)17β-(4-methyl -phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (26)17β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(27)17β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,(28) 17β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (29)17β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (30)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(31) N-t-Butyl-4-thia-5α-androst-1-en-3-one-16β-carboxamide, (32)16β-(1,5-dimethylhexyl)-7β-Methyl-4-thia-5α-androst-1-en-3-one, (33)16β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,(34) 16β-(N-tert-amylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (35)16β-(N-tert-hexylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (36)16β-(N-isobutylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (37)16β-(N-tert-octylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (38)16β-(N-1,1-diethylbutylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (39)16β-(N-neopentylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (40)16β-(N-2-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (41)16β-(N-1-adamantylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (42)16β-(N-2-norbomylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (43)16β-(N-1-norbomylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (44)16β-(N-phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (45)16β-(N-benzylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (46)16β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(47)16β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3one,(48)16β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(49)16β-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,(50)16β-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,(51)16β-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,(52) 16β-(N-n-octylcarbamoyl)-4-methyl-4-thia-5α-androst-1-en-3-one,(53) 16β-(1-methoxyethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one, (54)16β-(isopropyl)-7β-methyl-4-thia-5α-androst-1-en-3-one, (55)16β-(4-methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (56)16β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(57)16β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,(58) 16β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (59)16β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, and (60)16β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one.14. The compound of claim 13 selected from:(1)N-t-Butyl-4-thia-5α-androst-1-en-3-one-17β-carboxamide, (2)7β-Methyl-4-thia-5α-cholest-1-en-3-one, (3)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one,(4) 17β-(N-phenylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (5)17β-(N-benzylcarbamoyl)-4-thia-5α-androst-1-en-3-one, (6)17β-(1-methoxyethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one, (7)17β-(isopropyl)-7β-methyl-4-thia-5α-androst-1-en-3-one, (8)17β-(4-methylphenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (9)17β-(1-(3-chlorophenyoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(10)17β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,(11) 17β-(methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (12)17β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (13)17β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (14)17β-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(15) 16β-(4-methyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, (16)16β-(1-(3-chlorophenoxy)ethyl)-7β-methyl-4-thia-5α-androst-1-en-3-one,(17)16β-(4-methylsulfonyl-phenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one,(18) 16β-(4-chlorophenoxy)-7β-methyl-4-thia-5α-androst-1-en-3-one, and(19) 16β-(2-pyrimidinyloxy)-7β-methyl-4-thia-5α-androst-1-en-3-one.